Transduction of Hematopoietic Stem Cells for Enhanced Immunotherapy of Melanoma

造血干细胞转导增强黑色素瘤免疫治疗

• 批准号: 7782229
• 负责人: Donald B Kohn
• 金额: $ 29.49万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782229
• 关键词: Affect; Autologous; Avidity; Biodistribution; CD34 gene; Cell surface; Cells; Clinical; Clinical Trials; Collaborations; Complementary DNA; Development; Engineering; Exclusion; Experimental Models; Genes; Goals; Hematopoietic; Hematopoietic stem cells; Human; Human Engineering; Image; Immune system; Immunologics; Immunotherapy; In Vitro; Infusion procedures; Kinetics; Lead; Lentivirus Vector; Life; Lymphopoiesis; Malignant Neoplasms; Mature T-Lymphocyte; Melanoma Cell; Methods; Modality; Modeling; Mus; Nerve Growth Factors; Outcome; Patients; Peptides; Performance; Peripheral Blood Mononuclear Cell; Peripheral Blood Stem Cell; Phase I Clinical Trials; Positron-Emission Tomography; Pre-Clinical Model; Process; Production; Proteins; Public Health; Relative (related person); Reporter; Reporter Genes; Role; Safety; Source; Staging; Stem cells; Surface; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Time; Transgenic Organisms; Tumor Antigens; V(D)J Recombination; Variant; abstracting; base; cancer cell; cancer immunotherapy; cancer therapy; cell determination; cellular engineering; design; effective therapy; human embryonic stem cell; human subject; improved; in vivo; in vivo Model; melanoma; novel; novel strategies; peripheral blood; programs; receptor; response; stem; tumor; vector

PROJECT 3: TRANSDUCTION OF HEMATOPOIETIC STEM CELLS FOR ENHANCED IMMUNOTHERAPY OF MELANOMA. Project Leaders: Donald B. Kohn, James S. Economou, Antoni Ribas, Jerome A. Zack ABSTRACT Immunotherapy can be performed by expressing in T cells the genes encoding a T cell receptor (TCR) reactive against a tumor-associated antigen. This Project takes this approach, which is explored in Project 1, further by examining whether administration of hematopoietic stem cells (HSC) transduced with the genes encoding an anti-tumor TCR can lead to de novo production of T cells expressing the introduced TCR genes.. Theoretically, transduced HSC could serve as an additional long-term source of engineered T cells for sustained anti-tumor activity, to augment that of transduced mature T cells. We will develop and perform a Phase I clinical trial to assess the safety and feasibility of administering autologous CD34+ HSC transduced to express a TCR recognizing a peptide from MART-1 for immunotherapy of patients with advanced melanoma. These engineered CD34+ cells will be co-administered along with mature T cells transduced to express the same MART-1 TCR, but with a distinguishable reporter gene. This dual marking approach will allow identification, isolation and characterization of the TCR-expressing T cells produced in vivo from the CD34+ cells and determination of their in vivo biodistribution by using PET imaging. During the planning stage of the clinical trial, we will use pre-clinical models of human T cell production from HSC to perform detailed characterization of the T cells derived from transduced human HSC. Ongoing scientific collaborations will occur with all of the Projects and Cores of this Program. The clinical trial of this Project 3 will be performed in years 4-5 of this program, building on the clinical trial of Project 1 that defines the optimal methods for administration of the TCR-transduced T cells. These studies will assess the potential role of HSC for cancer immunotherapy using TCR-based approaches.

项目3：造血干细胞的转导 用于黑色素瘤的增强免疫治疗。 项目负责人：Donald B。作者：James S.放大图片作者：Economou，Antoni Ribas，杰罗姆A.扎克 摘要 免疫治疗可以通过在T细胞中表达编码T细胞受体（TCR）的基因来进行， 对肿瘤相关抗原具有反应性。本项目采用项目1中探讨的方法， 进一步通过检查施用转导有所述基因的造血干细胞（HSC）是否 编码抗肿瘤TCR的基因可以导致从头产生表达所引入的TCR基因的T细胞。 理论上，转导的HSC可以作为工程化T细胞的额外长期来源， 持续的抗肿瘤活性，以增强转导的成熟T细胞的抗肿瘤活性。我们将开发和执行一个 I期临床试验，以评估施用转导为CD 34的自体CD 34 + HSC的安全性和可行性。 表达识别来自MART-1的肽的TCR，用于晚期黑素瘤患者的免疫治疗。 这些工程化的CD 34+细胞将与经转导以表达CD 34 + T细胞的成熟T细胞一起沿着共同施用。 相同的MART-1 TCR，但具有可区分的报告基因。这种双重标记方法将允许 从CD 34 + T细胞体内产生的TCR表达T细胞的鉴定、分离和表征 细胞并通过使用PET成像确定它们的体内生物分布。在规划阶段， 在临床试验中，我们将使用从HSC产生的人类T细胞的临床前模型来进行详细的研究。 图10示出了来源于转导的人HSC的T细胞的特征。正在进行的科学合作将发生 与本计划的所有项目和核心。该项目3的临床试验将在几年内进行 4-5该计划的基础是项目1的临床试验，该试验定义了最佳的给药方法 TCR-转导的T细胞。这些研究将评估HSC在癌症免疫治疗中的潜在作用 使用基于TCR的方法。